Pesticide residues in food — 2006: Toxicological ... - ipcs inchem

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capsules. Some volunteers received only corn oil in gelatin capsules. The lowest dose used was
0.03 mg/kg bw, given initially to one volunteer receiving the test material and one receiving the
placebo. In the next phase, one volunteer received the placebo, six received diazinon at a dose of
0.03 mg/ kg bw and one received a dose of 0.12 mg/kg bw. In the next phase, one volunteer received the
placebo, six received diazinon at a dose of 0.12 mg/kg bw and one received a dose of 0.21 mg/ kg bw.
In the next phase, one volunteer received the placebo, six received diazinon at a dose of 0.21 mg/ kg bw
and one received a dose of 0.30 mg/kg bw. In the final phase, three volunteers received the placebo and
seven received diazinon at a dose of 0.20 mg/kg bw. A complete physical examination, including an
electrocardiogram, was carried out before and 2 days and 15 days after dosing. Vital signs (respiratory
parameters, oral temperature, blood pressure and pulse) were recorded before administration of the test
material and 1, 2, 4, 6, 8, 12, 24 and 48 h and 4, 7 and 14 days afterwards. The volunteers were asked
to report all adverse events. Blood was taken for clinical chemistry and haematological examination
before dosing and on days 1, 2 and 15 after dosing. Blood was collected 1 and 2 days and immediately
before dosing, and plasma and erythrocyte cholinesterase activity was determined by a modification of
the method of Ellman et al. (1961). Further samples for determination of cholinesterase activity were
taken 1, 2, 4, 6, 8, 12, 24 and 48 h after dosing and on days 5, 8 and 15 after dosing. Urine samples were
collected during 24 h before dosing and for 0–6, 6–12, 12–24 and 24–48 h after dosing.
The only self-reported adverse event considered to be related to intake of the test material
was back pain in a man at the highest dose. No treatment-related effects on haematological or
clinical chemical parameters were observed, except for changes in cholinesterase activity. Plasma
cholinesterase activity was inhibited by more than 20% at doses greater than 0.12 mg/kg bw. No
significant inhibition of erythrocyte cholinesterase activity was seen at any dose; at 0.21 mg/kg bw,
7% inhibition was observed at 4 h, 4% inhibition at 8 h and 6–7% inhibition at days 5, 8 and 15. At
other times, the erythrocyte cholinesterase activity was greater than or equal to that of the group given
the placebo. Furthermore, data for the man given the highest dose did not suggest any significant
inhibition of erythrocyte cholinesterase activity. The NOAEL was 0.21 mg/kg bw (the highest dose
was ignored, as only one man received it) (Meyer, 1999; Annex 1, reference 94; final version reported
as Anderson, 2000).
The results of the following study by Lazanas et al., (1966) were reported in an earlier
monograph (Annex 5, reference 7). Because of certain inaccuracies in that monograph, the study was
reviewed again and summarized below.
Three healthy adult male volunteers (Nos 4, 5 and 6) were given gelatin capsules containing
a mixture of diazinon 50W (50% w/w wettable powder; purity, 49.6%) and corn starch at a final
dose of 0.025 mg/kg bw per day administered as three doses per day, taken before meals at 08:00,
12:00 and 18:00, for 43 days. A concurrent control group of three volunteers (Nos 1, 2 and 3) were
given gelatin capsules containing corn starch only. In a second dosing regimen, three different
volunteers (Nos 1, 7 and 8) were treated as above at a dose of 0.020 mg/kg bw per day for 37 days.
In the recovery phase, after treatment at 0.025 mg/kg bw per day, volunteers were given capsules
containing corn starch only (placebo) for 101 days; this recovery phase was reduced to 41 days for
the group at 0.020 mg/kg bw per day. Plasma and erythrocyte cholinesterase activities in all eight
volunteers were measured on five separate occasions before dosing and then at intervals of 1–5
days throughout treatment and recovery using an electrometric method (Δ pH/h). Body weight
and clinical signs were monitored daily. Haematological parameters, including haemoglobin
concentration, erythrocyte count, total and differential leukocyte count and prothrombin time
were determined at intervals of 4–7 days during treatment and at 4–14 days during recovery, as
were clinical chemistry parameters, i.e. cholinesterase activity (erythrocytes and plasma), blood
urea nitrogen, alkaline phosphatase and alanine aminotransferase, and urine analysis, i.e. pH and
microscopic elements.
DIAZINON X-X JMPR 2006